Table of Contents
Prions are infectious agents that are very different from all the other pathogens you will encounter in this course. They contain no nucleic acids (no DNA, no RNA) and yet can multiply in an organism and cause severe, often fatal diseases of the nervous system. Understanding what makes them special helps to clarify where the limits of classical ideas about “living” pathogens lie.
What Are Prions?
The word “prion” comes from “proteinaceous infectious particle.” A prion is essentially:
- a misfolded form of a normal body protein, and
- capable of causing other copies of that same protein to adopt the same abnormal shape.
Key characteristics:
- Pure protein: no genome, no genes, no replication machinery of their own.
- Host-derived: the normal form of the protein (often called PrP\textsuperscript{C}, from “cellular prion protein”) is made by the host cell.
- Abnormal form: the disease-causing form is often written as PrP\textsuperscript{Sc} (from “scrapie,” a sheep disease). This abnormal form has the same amino acid sequence as PrP\textsuperscript{C}, but a different three-dimensional folding.
Because prions lack nucleic acids, they do not fit into the usual categories of viruses, bacteria, fungi, or protists.
Normal Versus Abnormal Prion Protein
Many cells in mammals, particularly neurons, produce the normal prion protein (PrP\textsuperscript{C}) and display it on their surface. Its exact physiological function is still not fully understood, but suggested roles include:
- involvement in cell signaling at the neuron surface
- potential function in protecting cells from oxidative stress
- roles in synaptic (nerve connection) maintenance
The disease-associated form, PrP\textsuperscript{Sc}:
- has the same primary structure (same amino acid sequence) as PrP\textsuperscript{C}
- has a different secondary and tertiary structure (more $\beta$-sheet content instead of $\alpha$-helix)
- is insoluble and tends to aggregate (clump together)
- is resistant to many proteases (enzymes that normally break down proteins)
This illustrates a fundamental concept: a change in protein folding alone, without any change in the underlying gene, can have dramatic biological consequences.
Mechanism of Prion Propagation
Prions “replicate” by a process best described as template-directed protein misfolding:
- A molecule of PrP\textsuperscript{Sc} (abnormal form) comes into contact with PrP\textsuperscript{C} (normal form).
- PrP\textsuperscript{Sc} binds to PrP\textsuperscript{C}.
- This interaction induces PrP\textsuperscript{C} to change shape and become PrP\textsuperscript{Sc}.
- Newly formed PrP\textsuperscript{Sc} molecules can in turn convert more PrP\textsuperscript{C}.
Over time, this leads to:
- Exponential amplification of the misfolded form.
- Formation of aggregates and amyloid fibrils that accumulate, especially in nervous tissue.
This is a form of information transfer without nucleic acid, where the “information” is the three-dimensional conformation (shape) of the protein.
Why Prions Are So Difficult to Destroy
Prions are unusually stable and resistant compared to most other infectious agents, because:
- Their abnormal $\beta$-sheet-rich structure makes them resistant to:
- heat (surviving temperatures that inactivate most viruses and bacteria),
- many chemicals (common disinfectants, formaldehyde),
- proteases that typically break down misfolded proteins.
- They can also adhere strongly to surfaces (metal instruments, for example).
Consequences for hygiene and medicine:
- Standard sterilization procedures (e.g., usual autoclaving, standard disinfection) may not be sufficient to inactivate prions.
- Special protocols are used in hospitals and laboratories for instruments suspected of prion contamination, often involving:
- higher temperatures and longer autoclaving times, and
- strong chemicals such as concentrated sodium hydroxide or sodium hypochlorite under defined conditions.
This resistance explains how prions could be transmitted by inadequately sterilized surgical instruments or medical materials in the past.
Pathology: How Prions Damage the Nervous System
Prion diseases primarily affect the central nervous system (brain and spinal cord). The accumulation of PrP\textsuperscript{Sc} and its aggregates leads to:
- Neuronal death (nerve cell loss)
- Spongiform degeneration: microscopic vacuoles (tiny holes) appear in brain tissue, giving it a sponge-like appearance
- Gliosis: proliferation of glial cells (support cells in the nervous system)
- Deposition of amyloid plaques formed from aggregated PrP\textsuperscript{Sc} in some forms of disease
Clinically, this results in:
- progressive dementia (decline in memory and cognitive ability)
- motor symptoms (ataxia, involuntary movements, muscle stiffness)
- behavioral and psychiatric changes
- ultimately coma and death
Prion diseases are slowly progressive: they often have a long incubation period (years to decades) between infection and onset of symptoms, but once symptoms appear, the course is usually rapid and fatal within months to a few years.
Prion Diseases in Humans
Prion diseases in humans are collectively called transmissible spongiform encephalopathies (TSEs). Important examples include:
Creutzfeldt–Jakob Disease (CJD)
CJD is the most common human prion disease. It comes in several forms:
- Sporadic CJD (sCJD):
- accounts for the majority of cases
- appears without any known cause
- likely arises from a random misfolding event of PrP\textsuperscript{C} into PrP\textsuperscript{Sc} or from an age-related failure of protein quality control
- Familial or genetic CJD:
- caused by inherited mutations in the prion protein gene ($PRNP$)
- mutations increase the tendency of PrP to misfold
- Iatrogenic CJD:
- transmitted through medical procedures, e.g.:
- contaminated neurosurgical instruments,
- corneal transplants,
- dura mater grafts,
- pituitary hormone preparations derived from human tissue (in the past).
- rare today due to improved safety protocols.
Typical features:
- rapid cognitive decline (dementia),
- movement disorders (myoclonus, ataxia),
- characteristic EEG or MRI changes,
- death usually within months.
Variant Creutzfeldt–Jakob Disease (vCJD)
vCJD is linked to bovine spongiform encephalopathy (BSE), also known as “mad cow disease.” It:
- affected primarily younger patients,
- was associated with consumption of contaminated beef products,
- shows somewhat different clinical and pathological features from “classical” CJD.
The emergence of vCJD revealed that some prions can cross the species barrier from animals to humans.
Gerstmann–Sträussler–Scheinker Syndrome (GSS)
- A rare, inherited prion disease.
- Caused by specific mutations in $PRNP$.
- Characterized by:
- progressive ataxia (loss of coordination),
- cognitive decline,
- distinctive amyloid plaques in the brain.
Fatal Familial Insomnia (FFI)
- Another inherited prion disease associated with specific $PRNP$ mutations.
- Main features:
- severe, progressive insomnia,
- autonomic disturbances (e.g. changes in blood pressure, heart rate),
- neuropsychiatric symptoms.
- Selectively affects regions of the brain involved in regulating sleep.
Kuru
- Historically described in the Fore people of Papua New Guinea.
- Transmitted through ritual cannibalism, particularly the consumption of brain tissue.
- Characterized by:
- trembling (hence the name “kuru,” meaning “shivering”),
- ataxia,
- emotional lability and inappropriate laughter (“laughing sickness”).
- Incidence fell dramatically after the end of the cannibalistic rituals, illustrating the infectious nature of prions.
Animal Prion Diseases and Transmission to Humans
Several prion diseases occur in animals:
- Scrapie in sheep and goats
- Bovine spongiform encephalopathy (BSE) in cattle
- Chronic wasting disease (CWD) in deer and elk
- Transmissible mink encephalopathy in farmed mink
These animal diseases are relevant for humans because:
- They reveal the zooanthroponotic potential of prions (transmission from animals to humans), as evidenced by BSE → vCJD.
- They raise questions about food safety, especially regarding tissues with high prion content (brain, spinal cord).
- They highlight that different prion “strains” can exist, even when they all involve the same prion protein.
Prion “Strains”
Surprisingly, different prion diseases—even within one species—can be caused by different conformations of the same prion protein:
- These conformations are called prion strains.
- Each strain has:
- its own preferred pattern of brain lesions,
- characteristic incubation times,
- specific biochemical properties (e.g. protease resistance pattern).
This demonstrates that information can be encoded in protein structure alone, not only in DNA or RNA sequence.
Origin and Routes of Infection
Prion diseases in humans can arise in three fundamentally different ways:
- Sporadic
- No identifiable cause; likely spontaneous misfolding.
- Example: most cases of sporadic CJD.
- Genetic (inherited)
- Mutations in the $PRNP$ gene are passed from parents to offspring.
- The altered PrP is more prone to misfold.
- Examples: familial CJD, GSS, FFI.
- Acquired (infectious)
- Exposure to external prions that then convert host PrP.
- Routes include:
- ingestion (e.g. contaminated food in vCJD, Kuru),
- contaminated medical materials (iatrogenic CJD),
- in theory, transfusion of contaminated blood (documented for vCJD).
The species barrier influences how easily prions can jump between different animals and humans. It depends on:
- the similarity of the PrP amino acid sequences between species,
- the particular conformation of the prion strain.
Diagnosis and Prevention
Diagnosis
Prion diseases are challenging to diagnose during life. Important aspects include:
- Clinical picture: rapidly progressive dementia, motor symptoms, characteristic age groups.
- Instrumental findings:
- characteristic changes in EEG or MRI for some forms,
- specific patterns in cerebrospinal fluid (CSF) proteins.
- Definitive diagnosis:
- traditionally required histopathological examination of brain tissue (post-mortem),
- newer molecular methods (e.g. amplification techniques for misfolded PrP) are being developed to improve ante-mortem diagnosis.
Prevention and Control
Because there is no effective cure for prion diseases, prevention is crucial:
- Food safety measures:
- banning high-risk tissues (e.g. bovine brain, spinal cord) from human food and some animal feeds,
- surveillance of livestock for prion diseases.
- Medical safety:
- strict sterilization protocols for neurosurgical instruments,
- avoiding reuse of materials that cannot be reliably decontaminated,
- using synthetic or recombinant products instead of human-derived preparations when possible.
- Genetic counseling for families with known $PRNP$ mutations.
Why Prions Matter for Biology
Prions are important for several broader reasons:
- They challenge the traditional division between living and non-living infectious agents.
- They demonstrate that protein folding is central to cell function and that misfolding can behave like an infection.
- They illustrate how epidemiology, genetics, biochemistry, and public health intersect in the management of disease.
- They have inspired new lines of research into other protein misfolding diseases (such as Alzheimer’s and Parkinson’s disease), which, while not infectious in the same way, share some principles of aggregation and toxicity.
Understanding prions thus deepens our view of what can act as a pathogen, and emphasizes the critical role of protein structure and stability in maintaining health.